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Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1

Helena Silva Cascales, Kamila Burdova, Anna Middleton, Vladislav Kuzin, Erik Müllers, Henriette Stoy, Laura Baranello, Libor Macurek, View ORCID ProfileArne Lindqvist
doi: https://doi.org/10.1101/191437
Helena Silva Cascales
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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Kamila Burdova
2Laboratory of Cancer Cell Biology; Institute of Molecular Genetics; Academy of Sciences of the Czech Republic; Prague, Czech Republic
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Anna Middleton
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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Vladislav Kuzin
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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Erik Müllers
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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Henriette Stoy
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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Laura Baranello
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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Libor Macurek
2Laboratory of Cancer Cell Biology; Institute of Molecular Genetics; Academy of Sciences of the Czech Republic; Prague, Czech Republic
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Arne Lindqvist
1Department of Cell and Molecular Biology; Karolinska Institutet; Stockholm, Sweden
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  • ORCID record for Arne Lindqvist
  • For correspondence: arne.lindqvist@ki.se
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Abstract

Cyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. Cyclin A2 participates in feedback loops that activate mitotic kinases in G2-phase, but why active Cyclin A2-CDK2 during S phase does not trigger mitotic kinase activation remains unclear. Here we describe a change in localisation of Cyclin A2 from being only nuclear to both nuclear and cytoplasmic at the S/G2 border. We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. Expression of predominately cytoplasmic Cyclin A2 or phospho-mimicking PLK1 T210D can partially rescue a G2 arrest caused by Cyclin A2 depletion. Cytoplasmic presence of Cyclin A2 is restricted by p21, in particular after DNA damage. Cyclin A2 chromatin association during DNA replication and additional mechanisms contribute to Cyclin A2 localisation change in G2 phase. We find no evidence that such mechanisms involve G2 feedback loops and suggest that cytoplasmic appearance of Cyclin A2 at the S/G2 transition functions as a trigger for mitotic kinase activation.

Synopsis Main mitotic kinases as PLK1 are activated at the S/G2 transition. A change in Cyclin A2 localisation at the S/G2 transition enables activation of PLK1.

Main points

  • -Cyclin A2 appears in the cytoplasm at the S/G2 transition

  • -Association with replicating chromatin and p21 restricts Cyclin A2 to the nucleus

  • -DNA damage ensures nuclear Cyclin A2 through p21

  • -Cytoplasmic Cyclin A2 initiates PLK1 activation

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Competing Interest Statement

Erik Mullers is an employee of AstraZeneca. Other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 29, 2020.
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Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1
Helena Silva Cascales, Kamila Burdova, Anna Middleton, Vladislav Kuzin, Erik Müllers, Henriette Stoy, Laura Baranello, Libor Macurek, Arne Lindqvist
bioRxiv 191437; doi: https://doi.org/10.1101/191437
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Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1
Helena Silva Cascales, Kamila Burdova, Anna Middleton, Vladislav Kuzin, Erik Müllers, Henriette Stoy, Laura Baranello, Libor Macurek, Arne Lindqvist
bioRxiv 191437; doi: https://doi.org/10.1101/191437

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